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Article: Carboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells

TitleCarboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
Authors
Issue Date2000
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2000, v. 275 n. 47, p. 36794-36802 How to Cite?
AbstractAbsence of functional presenilin 1 (PS1) protein leads to loss of γ-secretase cleavage of the amyloid precursor protein (βAPP), resulting in a dramatic reduction in amyloid β peptide (Aβ) production and accumulation of α- or β-secretase-cleaved COOH-terminal fragments of βAPP (α- or β-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as αAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Aβ-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length βAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of βAPP to the Golgi compartment is necessary before α- and β-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual γ-secretase catalytic activity or in other functions indirectly related to γ-secretase catalysis (e.g. an activator of γ-secretase, a substrate adaptor for γ-secretase, or delivery of γ-secretase to βAPP-containing compartments).
Persistent Identifierhttp://hdl.handle.net/10722/134763
ISSN
2014 Impact Factor: 4.573
2014 SCImago Journal Rankings: 2.734
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChen, Fen_HK
dc.contributor.authorYang, DSen_HK
dc.contributor.authorPetanceska, Sen_HK
dc.contributor.authorYang, Aen_HK
dc.contributor.authorTandon, Aen_HK
dc.contributor.authorYu, Gen_HK
dc.contributor.authorRozmahel, Ren_HK
dc.contributor.authorGhiso, Jen_HK
dc.contributor.authorNishimura, Men_HK
dc.contributor.authorZhang, DMen_HK
dc.contributor.authorKawarai, Ten_HK
dc.contributor.authorLevesque, Gen_HK
dc.contributor.authorMills, Jen_HK
dc.contributor.authorLevesque, Len_HK
dc.contributor.authorSong, YQen_HK
dc.contributor.authorRogaeva, Een_HK
dc.contributor.authorWestaway, Den_HK
dc.contributor.authorMount, Hen_HK
dc.contributor.authorGandy, Sen_HK
dc.contributor.authorSt GeorgeHyslop, Pen_HK
dc.contributor.authorFraser, PEen_HK
dc.date.accessioned2011-07-14T07:03:00Z-
dc.date.available2011-07-14T07:03:00Z-
dc.date.issued2000en_HK
dc.identifier.citationJournal Of Biological Chemistry, 2000, v. 275 n. 47, p. 36794-36802en_HK
dc.identifier.issn0021-9258en_HK
dc.identifier.urihttp://hdl.handle.net/10722/134763-
dc.description.abstractAbsence of functional presenilin 1 (PS1) protein leads to loss of γ-secretase cleavage of the amyloid precursor protein (βAPP), resulting in a dramatic reduction in amyloid β peptide (Aβ) production and accumulation of α- or β-secretase-cleaved COOH-terminal fragments of βAPP (α- or β-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as αAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Aβ-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length βAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of βAPP to the Golgi compartment is necessary before α- and β-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual γ-secretase catalytic activity or in other functions indirectly related to γ-secretase catalysis (e.g. an activator of γ-secretase, a substrate adaptor for γ-secretase, or delivery of γ-secretase to βAPP-containing compartments).en_HK
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_HK
dc.relation.ispartofJournal of Biological Chemistryen_HK
dc.subject.meshAlzheimer Disease/metabolismen_US
dc.subject.meshAmyloid Precursor Protein Secretasesen_US
dc.subject.meshAmyloid beta-Protein Precursor/*metabolismen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAspartic Acid Endopeptidasesen_US
dc.subject.meshBiological Markersen_US
dc.subject.meshBrain/metabolism/ultrastructureen_US
dc.subject.meshCell Compartmentationen_US
dc.subject.meshElectrophoresis, Polyacrylamide Gelen_US
dc.subject.meshEndopeptidases/metabolismen_US
dc.subject.meshMembrane Proteins/deficiency/*physiologyen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Knockouten_US
dc.subject.meshMicroscopy, Electronen_US
dc.subject.meshPeptide Fragments/*metabolismen_US
dc.subject.meshPresenilin-1en_US
dc.titleCarboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cellsen_HK
dc.typeArticleen_HK
dc.identifier.emailSong, YQ:songy@hkucc.hku.hken_HK
dc.identifier.authoritySong, YQ=rp00488en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1074/jbc.M006986200en_HK
dc.identifier.pmid10962005-
dc.identifier.scopuseid_2-s2.0-0034711207en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0034711207&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume275en_HK
dc.identifier.issue47en_HK
dc.identifier.spage36794en_HK
dc.identifier.epage36802en_HK
dc.identifier.isiWOS:000165577700051-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridChen, F=7404907428en_HK
dc.identifier.scopusauthoridYang, DS=7404800601en_HK
dc.identifier.scopusauthoridPetanceska, S=6603793144en_HK
dc.identifier.scopusauthoridYang, A=7203072322en_HK
dc.identifier.scopusauthoridTandon, A=7103281816en_HK
dc.identifier.scopusauthoridYu, G=35370376900en_HK
dc.identifier.scopusauthoridRozmahel, R=6701510561en_HK
dc.identifier.scopusauthoridGhiso, J=7006591910en_HK
dc.identifier.scopusauthoridNishimura, M=7403650959en_HK
dc.identifier.scopusauthoridZhang, DM=23017363200en_HK
dc.identifier.scopusauthoridKawarai, T=7003632751en_HK
dc.identifier.scopusauthoridLevesque, G=7006678462en_HK
dc.identifier.scopusauthoridMills, J=7402862038en_HK
dc.identifier.scopusauthoridLevesque, L=7007053389en_HK
dc.identifier.scopusauthoridSong, YQ=7404921212en_HK
dc.identifier.scopusauthoridRogaeva, E=35372614800en_HK
dc.identifier.scopusauthoridWestaway, D=7006295116en_HK
dc.identifier.scopusauthoridMount, H=7004279618en_HK
dc.identifier.scopusauthoridGandy, S=7006803448en_HK
dc.identifier.scopusauthoridSt GeorgeHyslop, P=7005637468en_HK
dc.identifier.scopusauthoridFraser, PE=35408135200en_HK

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